Acyl-Coenzyme A cholesterol acyltransferase (ACAT) is an enzyme that is capable of catalyzing synthesis of a cholesterol ester from cholesterol and plays an important role in the metabolism and absorption of cholesterol in the gastrointestinal tract.
In recent years, it has been reported that the plasma cholesterol level can be effectively suppressed by controlling the activity of ACAT present in the small intestine and the liver. So far, a number of studies have been carried out for ACAT inhibitors.
Meanwhile, the present inventors focused on ACAT in vascular wall and studied on the selective inhibitors against this type of ACAT. As a result, it was found that among azole compounds having a cyclic diamine structure, cyclic diamine compounds represented by the following formula (4): (wherein Ar represents an aryl group which may have a substituent(s)) were useful as therapeutic drugs for hyperlipidemia and arteriosclerosis, having less side effect and excellent oral absorption property. Based on such findings, the present inventors filed an international patent application (WO 98/54153).
In the above patent application, the compound (4) can be produced through the 5-step process of reactions as described below: (wherein Ar has the same meaning as defined above).
According to this reaction process, transformation of alcohol of the compound (1a) having an amino group protected by a tert-butoxy carbonyl group (Boc) into thioether is performed by a method in which the hydroxyl group is transformed to a methanesulfonyloxy group which readily leaves, followed by reacting with 2-mercaptobenzimidazole in the presence of a base. However, since the compound (1b) having such a leaving group has poor stability, by-products and decomposed products from the compound (1b) are readily generated during removal of the solvent included in post treatment of a large scale synthesis. As a result, it is difficult to avoid problems such as requirement of cumbersome purification procedures and variation in yield.
An object of the present invention is to provide an industrially advantageous process for producing a compound (4) serving as an ACAT inhibitor or a salt thereof. Another object of the invention is to provide a process for producing an intermediate therefor or a salt thereof.